Cabozantinib (XL-184) Monotherapy for Advanced Cholangiocarcinoma

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This research study is evaluating a drug called cabozantinib as a possible treatment cancer of the bile duct. Cabozantinib is a drug that targets specific pathways inside the cells of the body. By blocking the c-MET and VEGFR2 pathways from sending signals, cabozantinib may prevent cells from multiplying. This drug has been used in other research studies and information from those other research studies suggests that this drug may help to stop the growth of bile duct cancer.

In this research study, the investigators are looking to see how well cabozantinib works in slowing the growth of bile duct cancer. The investigators are also assessing the safety and tolerability of cabozantinib in participants with this type of cancer.

Patients will be treated with cabozantinib 60 mg daily administered orally continuously for 28-day cycles. Tumor assessments will be performed every 8 weeks until documented disease progression by RECIST criteria or drug intolerance.

Drug: Cabozantinib

Cabozantinib 60 mg (free base weight) per day will be administered daily and continuously for a cycle length of 28 days. Subjects will be provided with a sufficient supply of study treatment and instructions for taking the study treatment on days without scheduled clinic visits. After fasting (with exception of water) for 2 hours, subjects will take study treatment daily with a full glass of water (minimum of 8 oz/ 240 mL) and continue to fast for 1 hour after each dose of study treatment.

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Participants must have unresectable or metastatic histologically or cytologically confirmed intrahepatic cholangiocarcinoma or extrahepatic cholangiocarcinoma (i.e. hilar and distal cholangiocarcinoma).

Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan. See section 10 for the evaluation of measureable disease.

Participants must have failed at least 1 but no more than 2 lines of systemic regimens for advanced cholangiocarcinoma due to disease progression or toxicity.

Age ≥ 18 years.

Life expectancy of ≥ 3 months.

ECOG performance status < 1 (see Appendix A).

Participants must have adequate organ and marrow function as defined below:

Absolute neutrophil count > 1,500/mcL

Platelets > 100,000/mcL

Hemoglobin ≥ 9 g/dL

Total bilirubin ≤ 2.0 x the upper limit of normal

AST (SGOT)/ALT (SGPT) ≤ 5 X institutional upper limit of normal

PT/PTT ≤ 1.5 x ULN

Creatinine ≤ 1.5 or GFR ≥ 60 mL/min/1.73m2

Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis

Serum phosphorus, calcium, magnesium and potassium ≥ LLN

Urine protein: creatinine ratio ≤ 1

Serum Albumin ≥ 2.8 g/dl

Prior chemoembolization, radiofrequency ablation, or radiation to the liver is allowed as long as the patient has measurable disease outside of the treated area or measurable progression at the site of the treated area

Ability to understand and the willingness to sign a written informed consent document.

Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).

Women of childbearing potential must have a negative pregnancy test at screening. Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined as amenorrhea ≥ 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason.

Exclusion Criteria:

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.

Prior treatment with cabozantinib or other VEGF-R directed therapies

Gallbladder carcinoma or periampullary tumors

Chemotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin) or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

The subject has received radiation therapy:

to the thoracic cavity, abdomen or pelvis within 3 months of the first dose of study treatment or has with ongoing complications or is without complete recovery and healing from prior radiation therapy

to bone or brain metastasis within 14 days of the first dose of study treatment

to any other site(s) within 28 days of the first dose of study treatment

The subject has a primary brain tumor.

The subject has active brain metastases or epidural disease (Note: Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. (Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility.)

The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

Cardiovascular disorders including

Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening

Any of the following within 6 months before the first dose of study treatment:

abdominal fistula

gastrointestinal perforation

bowel obstruction or gastric outlet obstruction

intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 6 months before the first dose of study treatment.

Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy

Other clinically significant disorders such as:

active infection requiring systemic treatment within 28 days before the first dose of study treatment

serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment

history of organ transplant

concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment

history of major surgery as follows:

Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications

Minor surgery within 1 months of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications

Clinically significant gastrointestinal bleeding within six months of the first dose of study treatment

Previous history of pulmonary embolism or deep venous thrombosis

Severely impaired lung function or history of interstitial lung disease

Concurrent malignancy (other than adequately treated non-melanoma skin cancer, superficial transitional cell carcinoma of the bladder, and cervical carcinoma in situ) diagnosed within the past 3 years or any currently active malignancy

Psychiatric illness/social situations that would limit compliance with study requirements.

The subject has a history of clinically significant hematemesis, hemoptysis of > 2.5 mL of red blood, radiation (including brachytherapy) to pulmonary lesions, or signs indicative of significant pulmonary hemorrhage within 3 months before the first dose of study treatment.

The subject has radiographic evidence of cavitating pulmonary lesion(s)

The subject has a lesion abutting, invading, or encasing a major blood vessel.

The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.

The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.

The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before randomization. . Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard

History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib.

The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment. Note: Subjects with prostate cancer currently receiving LHRH or GnRH agonists may be maintained on these agents.

The subject is unable to swallow tablets

Individuals who are known to be HIV-positive are excluded from this study. HIV positive individuals are at increased risk of lethal infection when treated with marrow-suppressive agents, and cabozantinib has not adequately been tested in this population. Also, antiretroviral therapy may have pharmacokinetic interactions with cabozantinib that have not been fully characterized yet.

Pregnant women are excluded from this study due to the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with cabozatinib, breastfeeding should be discontinued if the mother is treated with cabozantnib. These potential risks may also apply to other agents used in this study.

Subjects may not be receiving any other study agents concurrently while on this study